Risk of Short-Term Prostate-Specific Antigen Recurrence and Failure in Patients With Prostate Cancer

Key Points Question What factors are associated with a shorter time interval to prostate-specific antigen (PSA) failure (PSA nadir plus 2 ng/mL or initiation of salvage therapies) in nonmetastatic unfavorable-risk prostate cancer? Findings In this secondary analysis of a phase 3 clinical trial with 350 participants, significant factors associated with shorter time to PSA failure were younger than 70 years, a PSA of 10 ng/mL or more, and a Gleason score of 8 to 10. A high-risk group, defined by these 3 factors, had 43.8% risk of PSA failure at 3 years. Meaning These findings suggest that males with unfavorable-risk prostate cancer who are at very high-risk for early PSA failure can be identified and may benefit from study in randomized treatment escalation studies.


Findings
Meaning These findings suggest that males with unfavorable-risk prostate cancer who are at very high-risk for early PSA failure can be identified and may benefit from study in randomized treatment escalation studies.

Introduction
2][3] However, despite definitive management, up to one third of the patients eventually experience biochemical recurrence. 4A current standard of care for patients seeking RT who have a nonmetastatic unfavorable-risk PC is external beam RT and ADT.Combination of ADT with the androgen receptor (AR)-signaling inhibitors, such as abiraterone, 5,6 enzalutamide, 7 apalutamide, 8 and darolutamide, 9,10 provides additional clinical benefits for males with advanced PC both in the castrate sensitive M1 and castrate resistance M0 disease states.5][16][17] Thus, there is a need for further study to identify the subgroup of unfavorable-risk PC patients who would benefit from the treatment intensification with AR-signaling inhibitors or cytotoxic chemotherapy.
The prognosis following prostate-specific antigen (PSA) failure in patients with localized PC treated with RT varies widely.9][20][21] In the Dana-Farber Cancer Institute (DFCI) 95-096 randomized clinical trial comparing RT alone with RT and 6-month ADT, Royce et al 19 reported that the interval to PSA failure of less than 30 months was a significant surrogate for all-cause mortality.
The time to PSA failure of less than 2 years was also linked to worse PC-specific survival in Trans-Tasman Radiation Oncology Group 96.01 trial. 20In addition, Dignam et al 21 reported that biochemical recurrence within 3 years is a surrogate to identify the OS benefits of long-term ADT in the secondary analysis of Radiation Therapy Oncology Group 92-02 trial.Given the clinical significance of the time interval to PSA failure, it is vital to identify the prognostic factors associated with early time recurrence.
With the advent of more advanced treatments, such as AR-signaling inhibitors and docetaxel, an opportunity exists for treatment escalation, yet for whom treatment escalation is most needed remains unknown.In the current study, we present a secondary analysis of DFCI trial 05-043 using individual patient data, evaluating the factors of shorter time interval to PSA failure (ie, within 3 years) to identify patients for treatment escalation randomized clinical trials.

Methods
This randomized clinical trial was approved by the institutional review board of the Dana-Farber/ Harvard Cancer Center and registered with ClinicalTrials.gov. 22This study follows the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.Informed consent was provided by all participants.Cooperative Oncology Group (ECOG) performance status of 0 or 1, and having adequate hematologic function with a white blood cell count more than 3000/mm 3 , platelet count of more than 105/mm 3 , and a hemoglobin count of more than 8.0 g/dL (to convert to g/L, multiply by 10.0).Furthermore, evidence of metastatic disease was assessed using radionuclide bone scan and computed tomography or magnetic resonance imaging, and males with no evidence of metastasis were considered eligible for enrollment.Participants with pelvic lymph nodes measuring up to 1.5 cm in long axis were permitted.Self-identified race was collected as a baseline characteristic during the enrollment process to assess potential disparities and differences in outcomes.

Patient Population and Treatment
As shown in Figure 1, the CONSORT diagram, patients were randomly assigned in a 1:1 ratio to receive either 6 months of ADT and RT or 6 months of ADT, RT, and 10 cycles of docetaxel.The PSA survival analysis included a total of 350 patients.All patients received in total 73.7 Gy (after 95% normalization) to the prostate and seminal vesicles using 3-dimensional conformal RT technique or intensity-modulated RT.Pelvic lymph nodes were treated at the discretion of the treating physician.
ADT consisted of a luteinizing hormone-releasing hormone agonist and antiandrogen.ADT was given as 2 months of neoadjuvant therapy, 2 months of concurrent therapy with RT, and 2 months of adjuvant therapy.A complete listing of eligibility criteria and treatment specifications is listed in the Trial Protocol in Supplement 2.

Follow-Up
After the end of treatment, males were followed up with every 6 months for the first 5 years and annually thereafter.A serum PSA was obtained at each follow-up.In addition to routine follow-up assessment, restating with a bone scan and pelvis magnetic resonance imaging or computed tomography were performed at the time of PSA failure.Salvage ADT was recommended when PSA levels rose to approximately 10 ng/mL.All patients were followed from the date of random assignment until death, and the cause of death was centrally reviewed.

Statistical Analysis
The baseline characteristics of the study cohort at the time of randomization were presented using descriptive statistics in a tabular format.The primary end point was time to PSA failure, defined as time from randomization to earliest date of PSA nadir plus 2 ng/mL or the initiation of salvage therapies, such as ADT, brachytherapy, or radical prostatectomy, or censored at the date of last disease assessment for those alive and without PSA failure.Deaths from non-PC causes were counted as competing risk events.
In this secondary analysis of a randomized clinical trial, the intent of the study was to assess the prognostic association between baseline clinical factors and time to PSA failure.Clinical factors

Patient Characteristics
The A total of 10 patients withdrew consent or were lost to follow-up during the study period.

Factors of Time to PSA Failure
The CIRs of PSA failure at The 3 significant factors associated with time to PSA failure were used to divide patients into 2 categories.The high-risk category was defined as being younger than 70 years, having a PSA of 10 ng/mL or higher, and having a Gleason score of 8 to 10. Otherwise, it was defined as low risk.Among the males in the high risk category, CIRs of PSA failure at 3 years was 43.8% (95% CI, 31.8%-55.2%)(eTable 2 in Supplement 1).As shown in Figure 2, CIR curves of PSA failure were significantly different between the 2 risk categories (5-year CIR: 60.5% ;95% CI, 47.6%-71.2%;vs 29.0%; 95% CI, 23.6%-34.5%;P <.001).In addition to higher clinical T stage and the use of pelvic radiotherapy, the high risk category (sHR, 2.69; 95% CI, 1.84-3.93;P < .001) was also associated with a shorter time to PSA failure (Table 3).

Discussion
In this study, we examined a cohort of males who experienced PSA failure after ADT and RT with or without docetaxel for nonmetastatic unfavorable-risk PC in the context of a randomized clinical trial.
We found 3 significant factors that were associated with a shorter time to PSA failure were being younger than 70 years, having a PSA of 10 ng/mL or more, and having a biopsy Gleason score of 8 to Of note, similar to a previously published randomized clinical trial, 23 the use of pelvic radiotherapy in our study was associated with a significant reduction in PSA recurrence.

JAMA Network Open | Oncology
Time to PSA failure was investigated in other retrospective and secondary analyses of males who received RT alone or RT with ADT.In these studies, a shorter time to PSA failure associated with PC-specific mortality, 18 all-cause mortality, 19 PC-specific survival, 20 and OS. 21To our knowledge, our study is novel because it is the first analysis combining factors of shorter time to PSA failure.The clinical significance of this study is that this information can be used to select males for a phase 3 Combination therapy of ADT and AR-signaling inhibitors leading to greater androgen suppression has been shown to improve clinical outcomes in males with nonmetastatic castrateresistant PC (nmCRPC).The addition of enzalutamide to ADT was found to prolong OS in males with nmCRPC, 24 and now the ongoing ENZARAD randomized clinical trial is investigating this combination in males with high-risk PC who are receiving RT. 25 Long-term data from the phase 3 SPARTAN trial, evaluated apalutamide and ADT vs ADT alone in males with nmCRPC, showed significant improvement in metastasis-free survival (MFS) with the combination. 8Similarly, the phase 3 ARAMIS trial revealed that darolutamide plus ADT improved OS compared with ADT alone. 26Given the  survival benefits observed in males undergoing either apalutamide or darolutamide therapy for nmCRPC and the worse clinical outcomes with a shorter time to PSA failure, one could consider a randomized clinical trial in which the males who were high-risk as defined in our study could be randomized to ADT plus RT with or without apalutamide and/or darolutamide.
Although the addition of docetaxel to ADT is currently not recommended for males with unfavorable-risk PC due to inconclusive results from previous randomized clinical trials, [14][15][16][17][27][28][29] a subgroup of males as defined by our study may benefit from and should be the subject of future randomized study. The Deipher risk score can also be an alternative strategy to guide treatment escalation for males with unfavorable-risk PC.A recently activated NRG-GU009 trial is now randomizing males with high-risk PC to either intensification or deintensification treatments based on the Decipher risk score.30 The use of molecular markers in risk stratification for PC is an active area of research with significant future potential.New tissue-based genomic tests, such as the Decipher, Prolaris, PTEN/TMPRSS2: ERG, Oncotype DX, ConfirmMDx, and ProMark, are being investigated to improve the detection and risk assessment of PC. 31 Future research will focus on validating these biomarkers and determining their effectiveness in guiding treatment decisions.Furthermore, the integration of molecular markers into clinical practice will require the development of guidelines and algorithms to facilitate their appropriate use in risk stratification and treatment planning.These advancements have the potential to enable more personalized treatment approaches, which is the subject of ongoing NRG-GU009 trial.

Limitations
This study has limitations.First, it is a secondary subgroup analysis, and therefore these results are hypothesis-generating and should be evaluated in a new cohort study.Second, our observation of the significant factors associated with the shorter time to PSA failure may not be applicable in treatment settings outside the one used in this study.Therefore, the question remains whether these factors are maintained in the postoperative settings.Third, it is important to recognize that the high ECOG performance status observed in this cohort, which was a requirement for inclusion in the initial trial design, may limit the generalizability of our findings to populations with different performance status profiles.Fourth, it is important to acknowledge that the study cohort primarily consisted of non-Hispanic White men, which may limit the generalizability of our findings to more racially diverse populations.Fifth, the patient's level of comorbidity may affect the survival benefit from the treatment intensification, and therefore future randomized clinical trials should consider prerandomization stratification by comorbidity level in addition to the high-risk group defined by our study.
In this secondary analysis of a phase 3 clinical trial with 350 participants, significant factors associated with shorter time to PSA failure were younger than 70 years, a PSA of 10 ng/mL or more, and a Gleason score of 8 to 10.A high-risk group, defined by these 3 factors, had 43.8% risk of PSA failure at 3 years.

3 and 5
years by clinical factors are shown in eTable 2 and illustrated in eFigure in Supplement 1.

Figure 2 .
Figure 2. Cumulative Incidence Curves of PSA Failure by Risk Categories 1.0

JAMA Network Open | Oncology Risk
of Short-Term PSA Recurrence and Failure in Prostate Cancer Patients

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invasion.Additional inclusion criteria included being 30 years or older, having an Eastern (categorically defined as younger than 60 years vs 60 to 69 years vs 70 years or older), PSA (categorically defined as less than 4 ng/mL vs 4 to less than 10 ng/mL vs 10 to 20 ng/mL vs more than 20 ng/mL), biopsy Gleason score (categorically defined as 8 to 10 vs 7 vs 6 or less), clinical T-category (categorically defined as T3-4 vs T2 vs T1), ECOG performance status (categorically defined as 1 vs 0) and use of pelvic RT.To fulfill this objective, for each baseline factor of interest, graphical cumulative incidence rate (CIR) curves of PSA failure were produced, treating non-PC deaths as competing events.A Gray test was used to compare these curves for each baseline clinical factor of interest.Meanwhile, the CIR estimates of PSA failure at 3 and 5 years were provided with 95% CIs.Furthermore, to more quantitatively evaluate the association of baseline clinical factors of interest with PSA failure, a multivariable competing risk regression for the subdistribution hazard ratio (sHR) using the Fine and Gray model was applied.The model is stratified by regions (US-Northeast, US-West, US-other, Australia, and New Zealand), and randomization arm.Statistical significance was defined as P < .05.All analyses were performed using SAS version 9.4 (SAS JAMA Network Open | OncologyRisk of Short-Term PSA Recurrence and Failure in Prostate Cancer Patients JAMA Network Open.2023;6(10):e2336390. doi:10.1001/jamanetworkopen.2023.36390(Reprinted) October 6, 2023 3/10 Downloaded From: https://jamanetwork.com/ on 10/09/2023 evaluated included age study population included 350 males with a median (range) age of 66 (43-86) years and included 4 Asian males (1.1%), 9 Black males (2.6%), 271 White males (77.4%), and 66 males (18.9%) who selected other as their race.In total, 167 males (46.6%) had a Gleason score of 8 to10 and 195 (55.2%) with baseline PSA of more than 10 ng/mL.Additionally, 330 males (94.3%) had a good performance status with an ECOG score of 0, as indicated in Table1.The median (IQR) follow-up was 10.2 (8.0-11.4)years.The overall sample size for the primary analysis included a total of 350 patients.

Table 2 .
Multivariable Competing Risk Regression Estimate of sHR for Biochemical Progression in Fine and Gray's Model a The multivariable model is also stratified by regions (US-Northeast, US-West, US-Other, Australia, New Zealand) and randomization arm.bAge was included in the model as a continuous variable; parameter and hazard ratios of age are shown in per 5-year increment.

Table 3 .
Multivariable Competing Risk Regression Estimate of sHR for Biochemical Progression in Fine and Gray Model Lin DW, Shih MC, Aronson W, et al.Veterans Affairs cooperative studies program study #553: chemotherapy after prostatectomy for high-risk prostate carcinoma: a phase III randomized study.Eur Urol.2020;77(5):563-572.doi:10.1016/j.eururo.2019.12.020 28.Fizazi K, Carmel A, Joly F, et al.Updated results of GETUG-12, a phase III trial of docetaxel-based chemotherapy in high-risk localized prostate cancer, with a 12-year follow-up.Ann Oncol.2018;29:viii271.doi:10.1093/annonc/mdy284 29.Eastham JA, Heller G, Halabi S, et al.Cancer and leukemia group B 90203 (Alliance): radical prostatectomy with or without neoadjuvant chemohormonal therapy in localized, high-risk prostate cancer.J Clin Oncol.2020;38 (26):3042-3050.doi:10.1200/JCO.20.00315 30.Two studies for patients with unfavorable intermediate risk prostate cancer testing less intense treatment for patients with a low gene risk score and testing a more intense treatment for patients with a higher gene risk score.ClinicalTrials.gov.Accessed April 21, 2023.https://clinicaltrials.gov/ct2/show/NCT05050084 31.Basourakos SP, Tzeng M, Lewicki PJ, et al.Tissue-based biomarkers for the risk stratification of men with clinically localized prostate cancer: mini review.Frontiers in Oncology.2021;11.doi:10.3389/fonc.2021.676716Time Intervals for PSA Failure in Prostate Cancer Studies eTable 2. The Cumulative Incidence Rates (CIR) of PSA Failure at 3 and 5 Years by the Clinical Factors eFigure.Cumulative Incidence Curves of PSA Failure by Age Group, PSA Levels, Gleason Score, 23 Clinical T Category, ECOG Performance Score, and Use of Pelvic RT a The multivariable model is also stratified by regions (US-Northeast, US-West, US-Other, Australia, New Zealand) and randomization arm.bThehigh-risk category was defined as being younger than age 70 years, a prostate-specific antigen of 10 ng/mL or more, and a Gleason score of 8 to 10.27.